title: ATR controls the UV-related upregulation of the CDKN1A mRNA in a Cdk1/HuR-dependent manner.
abstract: Ultraviolet (UV) light is a carcinogenic agent that upregulates the expression of several genes involved in various cellular processes, including cell cycle checkpoints and apoptosis. The universal cyclin-dependent kinase inhibitor p21(WAF1/Cip1) plays major roles in these processes, and the level of its corresponding message increases several times in response to UV-induced DNA damage. This upregulation is mainly posttranscriptional owing to HuR-dependent mRNA stabilization. Since the protein kinase Atr plays major roles during the cellular response to UV damage, we sought to investigate its possible implication in the stabilization of the p21(WAF1/Cip1) coding mRNA. We have shown that the UV-dependent accumulation of the CDKN1A mRNA is indeed under the control of the Atr protein kinase. Upon UV damage, Atr allows nuclear-cytoplasmic shuttling of the HuR protein, which binds the CDKN1A mRNA and reduces its turnover. This ATR-dependent effect is mediated through UV-related phosphorylation/inactivation of the Cdk1 protein kinase by Atr, which leads to the dissociation of HuR from Cdk1. Indeed, inhibition or shRNA specific knockdown of CDK1 in ATR-deficient cells enhanced the cytoplasmic level of HuR and restored the CDKN1A mRNA upregulation in response to UV damage. These results show that ATR stabilizes the CDKN1A message in response to UV damage through Cdk1-related cytoplasmic accumulation of HuR.
authors.affiliation: Department of Molecular Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Kingdom of Saudi Arabia; The Joint Center for Genomics Research, King Abdulaziz City for Science and Technology, Riyadh, Kingdom of Saudi Arabia.
authors.forename: Huda H
authors.initials: HH
authors.lastname: Al-Khalaf
authors.forename: Abdelilah
authors.initials: A
authors.lastname: Aboussekhra
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics; D016203:CDC2 Protein Kinase; D018797:Cell Cycle Proteins / Q000235:genetics; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D018844:Cyclin-Dependent Kinases / Q000235:genetics*; D003593:Cytoplasm / Q000235:genetics; D004249:DNA Damage / Q000235:genetics; D051959:ELAV Proteins / Q000235:genetics*; D000067780:ELAV-Like Protein 1; D006801:Humans; D010766:Phosphorylation / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics; D014466:Ultraviolet Rays; D015854:Up-Regulation / Q000235:genetics*
chemical_list: C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D012333:RNA, Messenger; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases
keywords: ATR; CDKN1A; Cdk1; HuR; UV light